Human cancer tissues are composed of cells which are the clonal product of the unregulated growth of single cells. As a result of the progressive adaptation of these cells for higher growth rates and reduced sensitivity to regulatory signals, they show significant alterations from the cells of the tissue in which they arose. Yet in spite of the alteration in cell physiology that generally accompanies the malignant state, many tumors do retain certain pre-cancer regulatory mechanisms. Thus, about 30 percent of patients with metastatic breast cancer respond to ovariectomy, adrenalectomy of hypophsectomy with objective evidence of tumor regression, suggesting that the continued proliferation of the cells of those malignancies required continuous estrogenic stimulation. Such tumors, therefore, appear to recognize and, indeed, require the same signals that act during the normal estrus cycle to induce the controlled hypertrophy and hyperplasia of the healthy uterus. We feel that study of these tumors, with their vestige of normal growth control will provide an important handle to dissect the nature of hormone-responsive and non-responsive tumor growth. Our first objective is to examine the nature and specificity of interaction of the estradiol-receptor complex with the components of chromatin, which we tentatively assume to be the nuclear hormone acceptor. Secondly, we wish to apply this information to an analysis of human and other mammalian endocrine tumors that do or do not respond to endocrine therapy. These studies will test our specific hypothesis that the repeated DNA sequences conspicuously present only in eukaryotic chromosomes have a role in the recognition and binding of the estradiol-receptor complex; and that this recognition and binding system may be altered in some mammary cancers.